Many naturally occurring alkaloids, including tropane alkaloids (e.g., atropine, scopolamine, cocaine) and morphinan alkaloids (e.g., morphine, codeine, oripavine, thebaine) contain a tertiary N-methylamine group (See FIG. 1). Modification of this N-methylamine group can have a profound effect on the pharmacological properties of the modified molecule. The synthesis of a wide range of clinically relevant molecules include replacing the N-methyl group with different alkyl groups. For example, the replacement of the N-methyl group for an N-allyl or an N-cyclopropylmethyl group N-demethylation/N-alkylation generates the potent opioid receptor antagonists naloxone and naltrexone. Naloxone is a potent pure opioid antagonist and is a first line treatment for patients experiencing an opioid overdose. In many countries it is necessitated to be in place whenever opioids are administered to reverse the effects of the narcotic agonists. Naltrexone, on the other hand, is primarily used for the management of opioid and alcohol dependence. N-Demethylation is also a significant step in the synthesis of mixed opioid agonist-antagonists such as nalorphine, nalbuphine and buprenorphine (See FIG. 1). The replacement of the N-methyl group with longer N-alkyl groups can provide or restore agonist activity. For example, N-phenethylnormorphine has a 10-fold greater potency than morphine itself.
A number of methods for the N-demethylation of tertiary amines are known. Some methods for the removal of the N-methyl group involve the use of reagents such as cyanogen bromide or chloroformates. The reactions involved with these methods produce cyanamides and carbamates, respectively, which can be readily hydrolyzed to the corresponding amines. Similar transformations can be achieved with diethyl azodicarboxylate or N-iodosuccinimide. These methods, however, use highly toxic and corrosive reagents in stoichiometric amounts and also generate stoichiometric amounts of waste products. N-Demethylation can also be achieved using N-oxides, but such use requires multiple steps. N-Demethylation using N-oxides is typically performed by oxidation of the alkaloid to the corresponding N-oxide, isolation of the N-oxide as the hydrochloride salt, and subsequent activation and decomposition of the N-oxide to the N-demethylated product.
Laboratory scale processes for the catalytic oxidative N-demethylation of morphine-type alkaloids in the presence of an oxidant, such as oxygen gas, are known. The practical application of these processes on a commercial scale is limited, in part, due to the fact that conventional batch reactors are poorly suited to address the distinct process challenges and safety risks associated with reactions with molecular oxygen. For example, gas-liquid reactions can be dominated by mass transfer effects and even short periods of poor gas-liquid mixing can adversely affect reaction kinetics and selectivity, or lead to irreversible decomposition of a catalyst. Furthermore, reactions with oxygen gas can be highly exothermic or result in fires or explosions in the presence of flammable solvents.
The present disclosure addresses these concerns by using a continuous process having high mass and heat transport capabilities and suitable for multi-phase and highly exothermic reactions. Gaseous reagents can be easily and accurately added and mixed into the liquid phase using flow-based systems. Importantly, combustion and explosion hazards are reduced because gaseous reagents can be dissolved in flammable organic solvents at high pressure, minimizing or eliminating the possibility of a head space and therefore the possibility of fire or explosion. Consequently, reactions can be performed under unusually harsh process conditions in a safe and controllable manner (i.e. high temperature/high pressure conditions).